Variant: NM_001204.7(BMPR2):c.1133G>T (p.Gly378Val)

CA350341667

812824 (ClinVar)

Gene: BMPR2

Condition: pulmonary arterial hypertension

Inheritance Mode: Autosomal dominant inheritance

UUID: 368e3c33-2763-454e-838d-189f8a79efb2

Approved on: 2025-01-03

Published on: 2025-01-03

HGVS expressions

NM_001204.7:c.1133G>T
NM_001204.7(BMPR2):c.1133G>T (p.Gly378Val)
NC_000002.12:g.202532589G>T
CM000664.2:g.202532589G>T
NC_000002.11:g.203397312G>T
CM000664.1:g.203397312G>T
NC_000002.10:g.203105557G>T
NG_009363.1:g.161263G>T
ENST00000374580.10:c.1133G>T
ENST00000638587.1:c.1064G>T
ENST00000374574.2:c.1133G>T
ENST00000374580.8:c.1133G>T
NM_001204.6:c.1133G>T

Uncertain Significance

• Met criteria codes: PM1 PM2_Supporting PP3

• Not Met criteria codes: PM5 BS1 BP4 PS1 PS4 BA1

Expert Panel

Pulmonary Hypertension VCEP

Criteria Specification Information

Criteria Specification: ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.1.0

Evidence submitted by expert panel

Pulmonary Hypertension VCEP

The c.1133G>T (p.Gly378Val) variant is a missense variant harboured in exon 9 of the BMPR2 gene, predicted to cause substitution of glycine to valine encoding the functionally relevant catalytic kinase domain but without functional evidence indicating critical or non-critical (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.828, AlphaMissense is 0.994 indicating pathogenicity (PP3_met). The variant has been reported only once in a PAH subject (PMID: 29650961) (PS4 not met). PS2 was not assessed due to lack of paternity data. Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1.0, 1/18/2024).

Met criteria codes

• PM1: The variant is located in the conserved catalytic kinase domain but without functional evidence indicating if it is a critical or non-critical amino acid residue.
• PM2_Supporting: The variant is absent from gnomAD v2.1.1 controls and v4.1.
• PP3: The REVEL prediction algorithm score is 0.828, AlphaMissense is 0.994 indicating pathogenicity.

Not Met criteria codes

• PM5: No other variants reported for this amino acid.
• BS1: The variant is absent from gnomAD v2.1.1 controls and v4.1.
• BP4: The REVEL prediction algorithm score is 0.828, AlphaMissense is 0.994 indicating pathogenicity.
• PS1: No other variants reported for this amino acid.
• PS4: The variant has been reported only once in a PAH subject (PMID: 29650961).
• BA1: The variant is absent from gnomAD v2.1.1 controls and v4.1.